Methylation of xanthine to form caffeine



Patented May 23,. 1950 METHYLATION F XAN'THINE 'ro FORM CAFFEINE WilliamE. Decker, Melrose Highlands, Mass., as-

signor to Technical Specialties Company, a corporation of MassachusettsNo Drawing. Application January 9, 1946, Serial No. 640,131

1 Claim.

The present invention relates to methylation, and more particularly to anovel methylation procedure.

For purposes of illustration, the invention will be described in itsapplication to the methylation of xanthine to form caffeine.

As is well known, caffeine is useful as an ingredient in beverages,medicines, etc. In the past, caffeine has been obtained by extractionfrom tea leaves and from the leaves and berries of coffee and cocoaplants. Although considerable research has been directed to thesynthesis of cafi'eine, so far as I am aware no commercially practicableprocess for this purpose has heretofore been developed. For example, theuse of dimethyl sulfate as a methylating agent for xanthine gives a goodyield of caffeine, but the product is toxic.

It is an object of the present invention to provide an improvedmethylation precedure. Another object is to provide an improved processfor methylating xanthine. Still another object is to provideimprovements in methods for the synthesis of caffeine.

By my process, xanthine may be methylated to form caffeine, preferablyby the use of novel methylating agents and novel methylation andcrystallization procedures. The xanthine may conveniently be formed bytreating guanine with an acid, then the excess acid in the resultingxanthine solution may be substantially neutralized and the methylationof the xanthine may be carried out in the same solution.

As a specific example of my process, the following may be given, itbeing understood that this detailed procedure is for illustrativepurposes only and is not to be construed in a limiting sense.

:Guanine in aqueous suspension is treated with hydrochloric acid to formxanthine. The acid is supplied in amount five times that theoreticallyrequired. The excess acid in the xanthine solution is then neutralizedwith sodium carbonate until the pH of the solution is brought to6.5-7.0. The xanthine may then be methylated by adding acetone andmethyl acetate directly to the neutralized xanthine solution and formingcafifeine in said solution.

The acetone and meth l acetate may be added separately or together. Themethyl acetate is preferably supplied in the ratio of approximately 12mols of methyl acetate to 1 mol of xanthine in the solution. The amountof acetone added is preferably approximately equal in volume to themethyl acetate.

Reducing the proportion of acetone will decrease the amount of xanthinewhich is methylated by a given amount of methyl acetate.

The resulting caffeine solution is primed or seeded with 0.5% by weightof methyl oxalate, calculated on the basis of the caffeine, or it may beseeded with caifeine crystals. Cafieine crystals may then be obtained bycooling the solution. The caffeine crystals so obtained are purified byfractional sublimation.

The resulting product is non-toxic synthetic cafieine suitable for humanconsumption.

The function of the acetone is believed to be to afiect the equilibriumof the reaction in a manner that will release the methyl group from themethyl acetate for methylation, but the invention, of course, is notlimited to this or any other theory.

Instead of forming xanthine by the action of hydrochloric acid uponguanine, guanine may be converted to xanthine with other known agents,for example with nitrous acid, or xanthine obtained from another sourcemay be used in the subsequent steps of my process.

Neutralization of the excess acid in the Jamthine solution of the aboveexample may be effected by the addition of any suitable alkali, forexample urea or sodium carbonate. It is sometimes preferable to use analkali which will not form a water-soluble salt with the acid present,so that the salt formed by the neutralization reaction Will notcrystallize out with the caffeine. However, when the caffeine ispurified by fractional sublimation, this precaution is not necessary.

Instead of recoverinng caffeine by cooling the solution, the solutionmay be evaporated.

Purification of the caifeine may be effected by recrystallization, butthis will generally be found less advantageous than purification byfractional sublimation.

When, in the appended claims, reference is made to neutralizing thexanthine solution, I do not mean that the pH must be brought to thepoint of exact neutrality, but it may be, for example, one-half to onepH unit on the acid Side.

Another application of my novel methylation procedure is in thepreparation of theobromine by methylating xanthlne.

The present application is a continuation in part of my co-pendingapplication Ser. No. 568,793, filed December 18, 1944, now abandoned.

I claim:

A process for the synthesis of cafleine which comprises convertingguanine to xanthine by treatment with hydrochloric acid, and then, inthe same reaction vessel and without recovering the xanthine from theresulting solution, neutralizing the excess acid to bring the pH of thesolution to 6.5 to 7.0, methylating the xanthine in the resultingsolution with acetone and methyl WILLIAM E. DECKER.

REFERENCES CITED The following references are of record in the file ofthis patent:

Chem. Abstracts 1928, p. 1139 citing J. Prakt. Chem.,vo1. 118, pages198-221 (1928).

Textbook of Organic Chemistry, by George H.

Richter (1938) pages 3'75 and 377.

